Abstract
The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects.
Highlights
Cationic Antimicrobial Peptides (CAMPs) are components of the biological defense system of microorganisms, plants, animals and humans [1,2,3]
This was achieved by means of helical wheel projections (Figure 1), and by sequence search using 2,259 antimicrobial peptides with proved activity deposited in the APD2 database [39]
It was interesting to observe that the two short variants Pandinin 2 (Pin2) [14] and Pin2 [17] had Minimal inhibitory concentrations (MIC) values of 11.9 and 11.6 mM towards M. tuberculosis H37Rv and MIC values of 6 and 14.8 mM against M. tuberculosis muti-drug resistant strain (MDR), respectively. These results show the feasibility for using short sequence CAMPs against pathogenic M. tuberculosis strains that have acquired resistance to commercial antibiotics
Summary
Cationic Antimicrobial Peptides (CAMPs) are components of the biological defense system of microorganisms, plants, animals and humans [1,2,3]. CAMPs with alpha-helical conformation share some common characteristics such as antimicrobial activities at low micromolar concentrations and alpha-helix conformation in hydrophobic environments [9,10,11]. They have potent antibacterial activities that made them promissory candidates to develop novel antibiotics because of their broad-spectrum activity towards multiresistant pathogenic Gram-positive and Gram-negative bacteria, as well as towards clinically important yeasts such as Candida albicans [12,13,14]. The proline ‘‘kink’’ is a structural characteristic of some CAMPs that confer them high pore-forming abilities Clear examples of such peptides are melittin [16], alamethicin [17] and pardaxin [18]. CAMPs such as Magainin 2 from the African
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